ClinVar Miner

Submissions for variant NM_000548.5(TSC2):c.1832G>A (p.Arg611Gln) (rs28934872)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000013205 SCV000255877 pathogenic Tuberous sclerosis 2 2014-07-24 criteria provided, single submitter clinical testing
GeneDx RCV000414340 SCV000491001 pathogenic not provided 2018-08-27 criteria provided, single submitter clinical testing The R611Q pathogenic variant in the TSC2 gene has been reported multiple times in association with tuberous sclerosis complex (TSC) (Au et al., 1998; Sancak et al., 2005; TSC2 LOVD). Functional studies indicate that R611Q disrupts the TSC1-TSC2 complex (Hoogeveen-Westerveld et al., 2011; Nellist et al., 2001; Nellist et al., 2005). The R611Q variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R611Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Additionally, other missense variants at the same codon (R611W) and in nearby residues (A607E, A614D, F615S) have been reported in association with TSC (Stenson et al., 2014; TSC2 LOVD), supporting the functional importance of this region of the protein.
Invitae RCV000013205 SCV000544351 pathogenic Tuberous sclerosis 2 2019-11-14 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 611 of the TSC2 protein (p.Arg611Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is not present in population databases (rs28934872, ExAC no frequency). This variant has been reported in many individuals affected with, and is considered a relatively common cause of, tuberous sclerosis complex (PMID: 9463313, 17304050, 15595939, 10205261). ClinVar contains an entry for this variant (Variation ID: 12397). Experimental studies have shown that this missense change prevents the phosphorylation of tuberin tyrosine residues, prevents TSC complex-dependent inhibition of mTOR activity, inhibits formation of the tuberin-hamartin complex, and abolishes tuberin chaperone function (PMID: 11741832, 21309039, 15483652, 26703369, 18854862). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000491426 SCV000579587 pathogenic Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family
Athena Diagnostics Inc RCV000414340 SCV000615886 pathogenic not provided 2019-06-14 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/281106 chr). Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Co-occurs with otherwise positive results less than expected. Damaging to protein function(s) relevant to disease mechanism. One de novo case with parental identity confirmed, one de novo case without parental identity confirmed.
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000013205 SCV000782399 pathogenic Tuberous sclerosis 2 2016-11-01 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000013205 SCV000840073 pathogenic Tuberous sclerosis 2 2017-12-04 criteria provided, single submitter clinical testing This c.1832G>A (p.Arg611Gln) variant in the TSC2 gene has been reported in multiple unrelated individuals with Tuberous Sclerosis (PMID: 9463313, 10570911, 15595939). Functional studies have shown that the p.Arg611Gln mutant tuberin protein (encoded by the TSC2 gene) has decreased interaction with its binding partner, hamartin, and is unable to inhibit the mTOR pathway properly (PMID: 11741832, 15483652, 15963462, 18302728, 18308511, 21309039). The c.1832G>A variant in TSC2 is not present in the general population. This c.1832G>A (p.Arg611Gln) variant in the TSC2 gene is classified as pathogenic.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000768118 SCV000899051 pathogenic Lymphangiomyomatosis; Focal cortical dysplasia type II; Tuberous sclerosis 2 2018-09-28 criteria provided, single submitter clinical testing TSC2 NM_000548.4 exon 17 p.Arg611Gln (c.1832G>A): This variant has been reported in the literature in several individuals with tuberous sclerosis, at least one of whom was determined to be de novo (Au 1998 PMID:9463313, van Eeghen 2013 PMID:22867869, Overwater 2016 PMID:27406250). This variant is not present in large control databases. This variant is present in ClinVar, with several labs classifying this variant as pathogenic (Variation ID:12397). Evolutionary conservation and computational predictive tools predict that this variant may impact the protein. Additionally, in vitro functional studies further support an impact to the protein (Nellist 2001 PMID:11741832, Nellist 2005 PMID:15483652). Furthermore, another variant at this same codon (p.Arg611Trp) has been reported in the literature in association with disease and has been seen by our lab in an individual with tuberous sclerosis, further supporting that this region has significance. In summary, this variant is classified as pathogenic based on the data above.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000414340 SCV001334512 pathogenic not provided 2020-02-01 criteria provided, single submitter clinical testing
Division of Genomic Medicine, Department of Advanced Medicine, Medical Research Institute,Kanazawa Medical University RCV000013205 SCV001423565 pathogenic Tuberous sclerosis 2 2020-07-10 criteria provided, single submitter clinical testing
OMIM RCV000013205 SCV000033452 pathogenic Tuberous sclerosis 2 2000-05-23 no assertion criteria provided literature only
OMIM RCV000055317 SCV000033453 pathogenic Lymphangiomyomatosis 2000-05-23 no assertion criteria provided literature only
Tuberous sclerosis database (TSC2) RCV000042946 SCV000066743 not provided Tuberous sclerosis syndrome no assertion provided curation
Tuberous sclerosis database (TSC2) RCV000055317 SCV000083537 not provided Lymphangiomyomatosis no assertion provided curation
SN ONGC Dept of Genetics and Molecular biology Vision Research Foundation RCV000013205 SCV000090404 not provided Tuberous sclerosis 2 no assertion provided not provided

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